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EC: Im talking with Dr. Chris Watts of the FDA. Whats your title?
CW: Team Leader for standards and technology, Office of Pharmaceutical Sciences (OPS).
EC: All these changes keep coming. OK now, heres a real tough question to start off with. How do you like your new digs over at the old Office of Naval Research facility?
CW: Theyre fantastic. I really like having most of our people in one location, especially for OPS.
EC: Instead of having people running around and telecommuting?
CW: Yes. Were waiting for generics to get out there and biotech products. But most of the CDER people are already there.
EC: Ive heard the laboratory facilities there are really outstanding.
CW: Yes, the laboratories are right there and we have a great lab space where we can do the process-based research using process equipment, not just lab-scale equipment.
EC: I was just telling Moheb [Nasr] that most people in the industry only see the regulatory face of FDA, but they dont realize, or never knew, the quality of people that you have working in the labs.
CW: True, and thats where Moheb came from.
EC: You could take any of these people and theyd be at home anywhere, at any university or industrial or academic research center anywhere in the world. I remember a fellow in Laurel a few years back doing MS MS MS work on estrogens, female replacement hormone research work At the time, MIT didnt have some of the equipment that he was using. It was really cutting-edge.
CW: Our labs, some of the people in St. Louis, we're going to present some great posters. Robbe has done some good work, and Chris Ellis, and the entire OTR lab staff. And did you know that we now have a new OTR director, too: Vince Vilker?
EC: Now everyone else will know, too. I get CDERs daily newsletter. It is a wonderful resource, especially for me as a consultant. I love to mine the CDER web site. I cant tell you how many excellent slides Ive found up there and referred to in my courses.
CW: And its all public information.
EC: Making the law transparent gives people a lot more confidence.
CW: It really helps do away with podium policies.
EC: Last year when you and Ali were kind enough to be interviewed for this magazine I guess hes off somewhere else in the world on another mission We cant be selfish and keep everyone from FDA here. There have been some changes Im assuming that a large number of other companies have given intent to do PAT. Youd said there were no plans to change the guidance or to reissue another PAT guidance. But I guess do it the best you can scientifically doesnt need to be improved.
CW: Absolutely. But we did get a lot of questions about PAT vs. QbD and whether the Agency was losing interest in PAT. If anything, were more interested in PAT than ever before. And its not just the new drugs. The most encouraging thing to me is well, consider IFPAC. In the four or five years that Ive been coming to this conference, the progression in the discussion on PAT in pharma has gone far beyond the academic exercise "This is what we could do, and this is what we may do to This is what weve done and this is what were going to do tomorrow and this, the next day.
EC: So were not doing what Ive always referred to as PAT by PowerPoint?
CW: Exactly. And, by the way, we use that phrase all the time. David Radspinner and I did a session just this morning. We said, when we put this session together, pharmas made significant progressions in applying PAT. We said, We know PAT by PowerPoint, but we want good, strong examples of what has actually been done. It was a good session, and there have been a couple of really strong sessions at this years conference.
EC: Originally in 1998 I was reminiscing with Moheb he was in an IFPAC session that I was organizing in San Diego. In those days, I had one session in the morning, and Rick Cooley had one in the afternoon, and that was it for the week. Everyone went off to the gaming tables or to Lake Las Vegas in between. But look at the program now, with all the three, four, five concurrent sessions. Large as I am, I cant split myself up to attend them all. It is almost frustrating. It has really exploded.
CW: You cant keep up with everything thats happening. The excitement for us is the variety of PAT projects. The perception in the industry is that the large pharma companies are the only ones doing PAT. In fact, while the large ones are obviously very active, we have some really great examples of PAT being done by smaller companies, by generics manufacturers.
EC: Other than by Ajaz's team at Sandoz?
CW: We also see more biotech examples. Its encouraging to see the breadth and depth of activity in the pharma industry.
EC: I see biotech more and more and am getting contacts here and abroad. I used to laugh about NIR. People used to ask me about three uses but PAT has given it new life. Tell me about EMEA. They seem to be pretty neutral regarding PAT. Theyre not against it, but theyre not pushing it like FDA.
CW: I know theyre active in it. Were all on the same page re: discussions of ICH Q8.There are no philosophical differences. Theyre supporting it, but different regions may have different regulations by which they have to operate. Moheb and Helen have both been very active in maintaining links with EMEA, meeting with EMEA and discussing PAT with them. On more than one occasion, PAT has been the specific subject of meetings.
EC: Tell me about E55. Helen Winkle had, at one point, talked about extending E55 to cover pharmaceutical manufacturing more broadly.
CW: I dont think were looking at standards in general but focusing on PAT for now. Im not sure we expected it to address every pharmaceutical manufacturing need.
EC: Its not a magic committee.
CW: ASTM is one of several organizations with which were establishing standards. Were developing processes in house so that we can do this We have limited resources just like everyone else, so the question for us is, How do we prioritize our efforts? That doesnt mean that Standard A from committee XYZ wont be useful. It may be something that is exactly what the industry needs, but there arent any regulatory implications.
Were trying to follow the example of some of our sister organizations here in FDA, like the Center for Foods and the Center for Devices. Devices probably has the most noted consensus standards setting program of any at FDA. Were trying to bring all that to pharma.
Janet Woodcock heads the Council of Pharmaceutical Quality. A standard working group is part of that Council and is working on standards setting and the development of procedures for pharma products. We need to maintain not only the spirit but the action of the NTTAA A 19 1 circular.
EC: You know me as a bit of a gadfly and an impatient person. Someone invited me to join that group and my response was, I understand that there are openings now because several key people on that committee had been run down by a glacier. In all seriousness, given my temperament and the fact that Im not 50 or even 60 anymore I may not be getting directly involved, long term, but I enjoy talking to people like you and Moheb and learning what is going on...
CW: E55 is focusing specifically on standards for implementing PAT. I m kind of like you. I want things to be done yesterday. But the advantage that E55 offers is the open discussion of issues. Its not just one corner of the industry, or just industry, the academics, or just regulators. Everyone, including consumer groups, are involved and decide what we need in order to move forward and how to develop standards so that we minimize the work for ourselves.
EC: After all, were not talking about Frisbees here, were talking about drugs and peoples health, so these standards are important. One of the most encouraging things for people who used to think of FDA as the stodgy old policeman is the fact that theyre seeing young people like you and Ali, the younger faces, out there pushing these programs. Its encouraging. Ive been very impressed by the quality of personnel theyre getting the people at CDER, the Agencys younger scientists, mathematicians and chemometricians. Its a newer face. Its not, "Well, I cant do anything else, so let me work for FDA." Or Ive retired let me go to USP. Its a real career and you, as a group, seem to take an active approach that, We can do something.
CW: Thank you for including me in that younger group. I cant tell you how much Ive learned from my colleagues, including new colleagues, within OPS. Ive had the good fortune and pleasure of working very closely with seasoned investigators, who have seen whats happening and how things are changing specifically regarding PAT. We are really dedicated to the public health mission. I know that it may sound corny at times, but I cant speak highly enough of my colleagues.
Its like I always tell people in the industry who work in the QC function (which is usually described as a routine dull job) "Youre the last line of defense. You are our protectors." But at FDA, you set the standards and encourage the QA and QC people to make sure standards are met.
EC: So, are you seeing things happen faster and faster with regard to PAT, or is activity leveling out?
CW: Im encouraged by the level of activity. I try not to put numbers on anything because theyre not the best metric. Some of the things that were talking about you may not see in commercial products tomorrow or the next day. But the basic principles and understanding are being gained from implementing QbD and PAT in the R&D environment and you just cant put a number on that.
EC: Companies are doing it gladly?
CW: Exactly. Some of what weve approved wont necessarily see the light of day. There are some wonderful examples.
EC: You cant talk about it unless the company does. But you gave some numbers last year at Colgate?
CW: Weve amended those numbers. To call them approvals is a bit of a leap. Were at seven or eight, and some are in pilot program. All pilot program projects have incorporated PAT QbD pieces, the metrics, the understanding and the active control. Its blossoming, as you see in meetings like IFPAC. Its no longer theoretical. Were seeing really practical examples of whats happening in the industry.
EC: If its just a piece, we dont count it. So there may be 100 more companies doing raw materials by NIR and another 50 companies just doing moisture or blend uniformity which doesnt qualify as full PAT program, but still show that industry is assembling the building blocks that it will need for PAT programs in the future.
CW: Thats just it. Weve been encouraging people, telling people in the industry for some time that they dont have to eat the elephant in one bite. We suggest that they implement PAT in a piecemeal way.
We have Sanofi Aventis example as a great case history on implementing PAT for the entire manufacturing process from end to end, but others are just as good and they focus on specific unit operations or a problem that theyre having. For instance, theyre interrogating the unit operation to understand fully whats happening as theyre processing their materials.
EC: Moheb and I talked briefly about layoffs in some of the bigger companies recently in the industry. Over the years, Ive seen that pharma corporate management is hesitant to come up with bucks for something that they havent heard of. And I remember butting heads with Ajaz, who had come from academia and sometimes advocated eating the elephant. Having come from industry, I knew that if you can prove the concept to management with moisture or blending or raw materials, then you get approval and funding for the next step. Prove it then move on from there.
CW: Low hanging fruit is one good way to characterize it. Looking at moisture with spectroscopic techniques may not be new and novel in and of itself, but its novel to us, as an industry, to use that information to actively control a manufacturing process.
EC: If you can get rid of a Karl Fischer with all its inherent chemical waste, why not?
CW: We hear the characterization all the time that weve dropped this test or dropped that test, and thats not the case at all. Weve not dropped anything but simply moved the analysis and control on line or in line. You dont necessarily need the lab analysis.
EC: Youre doing 1000 where you used to do three. When I hear people saying Gee, Im afraid of doing something new, my response is always, Trust me on this. FDA is always happier when you do more tests. So if you now go to 5000 online tests instead of 10 tablets, theyll be happy if you do it right. More testing has never hurt FDAs feelings.
CW: Not just more, but the right analysis, is critical. Some companies have been giving us some great case studies, but we still may be looking at some things unnecessarily. For instance, theyll throw an analyzer on line and give us data from that analyzer, just because someone else has used that type of analyzer. It may not give us the info we need to control the quality of this product. So its focused analysis and control, rather than just doing a lot of different things because we can.
EC: It appears that we still need to dispel a lot of PAT urban legends. Someone just yesterday asked whether FDA were mandating PAT, and If I use it on one process, will I have to use it on all of them?"
CW: Those questions are legitimate, and we still hear them from time to time, but the program is still completely voluntary. Theres no mandate whatsoever, and were actively encouraging people to piecemeal their PAT implementations.
You dont have to do everything from soup to nuts, from raw material and API to finished product. There are great examples that take that approach, but you can just focus on a key unit operation, or a specific issue, and the limited approach can work very well too.
EC: The other myth I had to settle was that some people at a client company believed that if they put any kind of a monitor on equipment in a production setting, theyd have to immediately report every single data point to the Agency. I had to convince them that R&D data are not reported every day.
CW: Oh, yes. The whole concept of research data. That topic was the subject of much discussion in advisory committee meetings. We tried to be as clear as possible on the guidance documents. Even though its being used on an existing manufacturing process, as long as you do the risk assessment, and the analysis being done in line or on line doesnt have a negative impact on product quality, you dont have to come back to the Agency with all that data. After all, at that point, you dont even know whether the analyzer will give you the info youre looking for.
EC: Ive used the following analogy. Its like installing a new HPLC column. You dont have to report it if you dont use it.
CW: People ask: "If I put it on, and the information is useful, does that mean that I cant use it?" If you want to use the information from the R&D stage to justify an approach that youre taking, thats exactly the way things should evolve.
EC: So, tell me, is QbD easier for existing or new products?
CW: For existing products, we're really talking about Quality by Redesign. With true QbD were talking about products being developed now, and we may not see applications in four, five, six or seven years. We expect the implementation to take a while.
EC: Industry is used to seven-year timelines, anyway.
CW: But its not that principles dont apply to existing products. Weve seen from the pilot program, good and hard examples of practical implications of Q8 and Q9 that show how it translates for existing products and processes. But thats more like a redesign, and part of the "continual improvement" process.
EC: I guess well have our little tete-a-tete again next year?
CW: I will look forward to it.